Inhibition of tumor angiogenesis is an anticancer strategy that has gained widespread support from biologists and clinicians. In 1971, Dr. Judah Folkman introduced the concept of an “angiogenic switch” driving tumor growth and malignant progression. There have since been numerous scientific reports confirming the central concept that tumor growth is angiogenesis-dependent. Angiogenesis can occur under “normal” physiological conditions, such as during growth and development or wound healing, as well as under “pathological” conditions, such as in the transition of tumors from a dormant state to a malignant state. The dependency of solid tumors on new vessel growth has made tumor vessels an appealing target for cancer therapy.
Angiogenesis-based tumor therapy has several theoretical advantages over traditional cancer therapies (such as radiation and chemotherapy). Anti-angiogenesis therapy targets endothelial cells that line tumor vessels instead of the tumor cells themselves. Tumor cells evolve resistance to cancer therapies due to genomic instability (high variation) and rapid generation time (days). In contrast, endothelial cells have a higher genomic stability (low variation) and a longer generation time (months) compared to tumor cells. Endothelial cells are less likely to “escape” therapy because they will not undergo mitosis at such a rapid rate and carry any drug resistance variation through to the next generation within the lifespan of the therapy. Thus, the genomic stability of endothelial cells coupled with their longevity make them an attractive target for therapies directed against them.
Tumor endothelial markers (TEMs) were reported by St. Croix et al. (Science, 289: 1197-1201, 2000). St. Croix et al. employed serial analysis of gene expression (SAGE™) technology to compare small populations of normal and tumor-derived endothelial cells. The comparison revealed 79 genes that are potentially involved in angiogenesis. Of these, 46 genes were specifically expressed at least ten times higher in tumor-associated endothelium as compared to normal endothelium from the same patient.
The use of targeted drug delivery to inhibit tumor growth by interfering with angiogenesis has recently proven to be successful. For example, bevacizumab (Avastin®), an antibody that neutralizes vascular endothelial growth factor (VEGF; one of the many proteins involved in the development of a new network of blood vessels), has been approved by the FDA to treat colorectal cancer. A remaining challenge, however, is to identify markers that can differentiate pathological and physiological angiogenesis in order to selectively deliver therapeutic agents to diseased tissues while minimizing the potential side effects of the targeted therapy.